Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice.

Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of "inflammaging" Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti-microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging. Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions. Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression. Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes.

The Human Microbiome and Its Role in Musculoskeletal Disorders.

Musculoskeletal diseases (MSDs) are characterized as injuries and illnesses that affect the musculoskeletal system. MSDs affect every population worldwide and are associated with substantial global burden. Variations in the makeup of the gut microbiota may be related to chronic MSDs. There is growing interest in exploring potential connections between chronic MSDs and variations in the composition of gut microbiota. The human microbiota is a complex community consisting of viruses, archaea, bacteria, and eukaryotes, both inside and outside of the human body. These microorganisms play crucial roles in influencing human physiology, impacting metabolic and immunological systems in health and disease. Different body areas host specific types of microorganisms, with facultative anaerobes dominating the gastrointestinal tract (able to thrive with or without oxygen), while strict aerobes prevail in the nasal cavity, respiratory tract, and skin surfaces (requiring oxygen for development). Together with the immune system, these bacteria have coevolved throughout time, forming complex biological relationships. Changes in the microbial ecology of the gut may have a big impact on health and can help illnesses develop. These changes are frequently impacted by lifestyle choices and underlying medical disorders. The potential for safety, expenses, and efficacy of microbiota-based medicines, even with occasional delivery, has attracted interest. They are, therefore, a desirable candidate for treating MSDs that are chronic and that may have variable progression patterns. As such, the following is a narrative review to address the role of the human microbiome as it relates to MSDs.

An open label, non-randomized study assessing a prebiotic fiber intervention in a small cohort of Parkinson's disease participants.

A pro-inflammatory intestinal microbiome is characteristic of Parkinson's disease (PD). Prebiotic fibers change the microbiome and this study sought to understand the utility of prebiotic fibers for use in PD patients. The first experiments demonstrate that fermentation of PD patient stool with prebiotic fibers increased the production of beneficial metabolites (short chain fatty acids, SCFA) and changed the microbiota demonstrating the capacity of PD microbiota to respond favorably to prebiotics. Subsequently, an open-label, non-randomized study was conducted in newly diagnosed, non-medicated (n = 10) and treated PD participants (n = 10) wherein the impact of 10 days of prebiotic intervention was evaluated. Outcomes demonstrate that the prebiotic intervention was well tolerated (primary outcome) and safe (secondary outcome) in PD participants and was associated with beneficial biological changes in the microbiota, SCFA, inflammation, and neurofilament light chain. Exploratory analyses indicate effects on clinically relevant outcomes. This proof-of-concept study offers the scientific rationale for placebo-controlled trials using prebiotic fibers in PD patients. ClinicalTrials.gov Identifier: NCT04512599.

Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.

BACKGROUND: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. METHODS: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. RESULTS: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). CONCLUSIONS: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota-derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

Disruption of peripheral circadian rhythms of the colon epithelium results in worse colitis and increased intestinal permeability in mice when given dextran sulfate sodium. This may be mediated through alterations in microbiota, butyrate levels, and STAT3.

Alcohol use disorder as a potential risk factor for COVID-19 severity: A narrative review.

In Dec. 2019-January 2020, a pneumonia illness originating in Wuhan, China, designated as coronavirus disease 2019 (COVID-19) was shown to be caused by a novel RNA coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). People with advanced age, male sex, and/or underlying health conditions (obesity, type 2 diabetes, cardiovascular disease, hypertension, chronic kidney disease, and chronic lung disease) are especially vulnerable to severe COVID-19 symptoms and death. These risk factors impact the immune system and are also associated with poor health, chronic illness, and shortened longevity. However, a large percent of patients without these known risk factors also develops severe COVID-19 disease that can result in death. Thus, there must exist risk factors that promote exaggerated inflammatory and immune response to the SARS-CoV-2 virus leading to death. One such risk factor may be alcohol misuse and alcohol use disorder because these can exacerbate viral lung infections like SARS, influenza, and pneumonia. Thus, it is highly plausible that alcohol misuse is a risk factor for either increased infection rate when individuals are exposed to SARS-CoV-2 virus and/or more severe COVID-19 in infected patients. Alcohol use is a well-known risk factor for lung diseases and ARDS in SARS patients. We propose that alcohol has three key pathogenic elements in common with other COVID-19 severity risk factors: namely, inflammatory microbiota dysbiosis, leaky gut, and systemic activation of the NLRP3 inflammasome. We also propose that these three elements represent targets for therapy for severe COVID-19.

The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells.

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the "Cytokine Storm", which is a dramatic increase in inflammatory cytokines in the blood. In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or "Long COVID". Therefore, there is an urgent need to better understand the mechanisms of the virus. The spike protein on the surface of the virus is composed of joined S1-S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm. In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC.

Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a devastating neurodegenerative disorder. While genetics are important in the development of AD, environment and lifestyle are also important factors influencing AD. One such lifestyle factor is alcohol consumption. Unhealthy and excessive chronic alcohol consumption is associated with a greater risk of all types of dementia, especially AD. Alcohol consumption has numerous effects on the body, including alterations to the intestinal microbiota (dysbiosis) and intestinal barrier dysfunction (leakiness and intestinal hyperpermeability), with evidence indicating that inflammation resulting from dysbiosis and barrier dysfunction can promote neuroinflammation impacting brain structure and function. Objective: This study sought to determine the impact of alcohol-induced dysbiosis and barrier dysfunction on AD-like behavior and brain pathology using a transgenic rodent model of AD (3xTg-AD). Methods: Alcohol (20%) was administered to 3xTg-AD mice in the drinking water for 20 weeks. Intestinal (stool) microbiota, intestinal barrier permeability, systemic inflammation (IL-6), behavior, and AD pathology (phosphorylated tau and ß-amyloid), and microglia were examined. Results: Alcohol consumption changed the intestinal microbiota community (dysbiosis) and increased intestinal barrier permeability in both control and 3xTg-AD mice (oral/urine sugar test and lipopolysaccharide-binding protein (LBP)). However, alcohol consumption did not influence serum IL-6, behavior, or ß-amyloid, phosphorylated tau, or microglia in 3xTg-AD mice. Important differences in genotype and sex were noted. Conclusion: Alcohol-induced microbiota dysbiosis and intestinal barrier dysfunction did not exacerbate behavior or AD-like brain pathology in the 3xTg-AD mouse model of AD which could, in part, be the result of a lack of systemic inflammation.

Intestinal Barrier Dysfunction in the Absence of Systemic Inflammation Fails to Exacerbate Motor Dysfunction and Brain Pathology in a Mouse Model of Parkinson's Disease.

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease associated with aging. PD patients have systemic and neuroinflammation which is hypothesized to contribute to neurodegeneration. Recent studies highlight the importance of the gut-brain axis in PD pathogenesis and suggest that gut-derived inflammation can trigger and/or promote neuroinflammation and neurodegeneration in PD. However, it is not clear whether microbiota dysbiosis, intestinal barrier dysfunction, or intestinal inflammation (common features in PD patients) are primary drivers of disrupted gut-brain axis in PD that promote neuroinflammation and neurodegeneration. Objective: To determine the role of microbiota dysbiosis, intestinal barrier dysfunction, and colonic inflammation in neuroinflammation and neurodegeneration in a genetic rodent model of PD [α-synuclein overexpressing (ASO) mice]. Methods: To distinguish the role of intestinal barrier dysfunction separate from inflammation, low dose (1%) dextran sodium sulfate (DSS) was administered in cycles for 52 days to ASO and control mice. The outcomes assessed included intestinal barrier integrity, intestinal inflammation, stool microbiome community, systemic inflammation, motor function, microglial activation, and dopaminergic neurons. Results: Low dose DSS treatment caused intestinal barrier dysfunction (sugar test, histological analysis), intestinal microbiota dysbiosis, mild intestinal inflammation (colon shortening, elevated MPO), but it did not increase systemic inflammation (serum cytokines). However, DSS did not exacerbate motor dysfunction, neuroinflammation (microglial activation), or dopaminergic neuron loss in ASO mice. Conclusion: Disruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice.

Gut microbial metabolites in Parkinson's disease: Association with lifestyle, disease characteristics, and treatment status.

There is growing appreciation of the importance of the intestinal microbiota in Parkinson's disease (PD), and one potential mechanism by which the intestinal microbiota can communicate with the brain is via bacteria-derived metabolites. In this study, plasma levels of bacterial-derived metabolites including trimethylamine-N-oxide (TMAO), short chain fatty acids (SCFA), the branched chain fatty acid isovalerate, succinate, and lactate were evaluated in PD subjects (treatment naïve and treated) which were compared to (1) population controls, (2) spousal / household controls (similar lifestyle to PD subjects), and (3) subjects with multiple system atrophy (MSA). Analyses revealed an increase in the TMAO pathway in PD subjects which was independent of medication status, disease characteristics, and lifestyle. Lactic acid was decreased in treated PD subjects, succinic acid positively correlated with disease severity, and the ratio of pro-inflammatory TMAO to the putative anti-inflammatory metabolite butyric acid was significantly higher in PD subjects compared to controls indicating a pro-inflammatory shift in the metabolite profile in PD subjects. Finally, acetic and butyric acid were different between PD and MSA subjects indicating that metabolites may differentiate these synucleinopathies. In summary, (1) TMAO is elevated in PD subjects, a phenomenon independent of disease characteristics, treatment status, and lifestyle and (2) metabolites may differentiate PD and MSA subjects. Additional studies to understand the potential of TMAO and other bacterial metabolites to serve as a biomarker or therapeutic targets are warranted.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

PURPOSE OF REVIEW: Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. RECENT FINDINGS: There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

Abnormal intestinal milieu in posttraumatic stress disorder is not impacted by treatment that improves symptoms.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder, resulting from exposure to traumatic events. Current recommended first-line interventions for the treatment of PTSD include evidence-based psychotherapies, such as cognitive processing therapy (CPT). Psychotherapies are effective for reducing PTSD symptoms, but approximately two-thirds of veterans continue to meet diagnostic criteria for PTSD after treatment, suggesting there is an incomplete understanding of what factors sustain PTSD. The intestine can influence the brain and this study evaluated intestinal readouts in subjects with PTSD. Serum samples from controls without PTSD (n = 40) from the Duke INTRuST Program were compared with serum samples from veterans with PTSD (n = 40) recruited from the Road Home Program at Rush University Medical Center. Assessments included microbial metabolites, intestinal barrier, and intestinal epithelial cell function. In addition, intestinal readouts were assessed in subjects with PTSD before and after a 3-wk CPT-based intensive treatment program (ITP) to understand if treatment impacts the intestine. Compared with controls, veterans with PTSD had a proinflammatory intestinal environment including lower levels of microbiota-derived metabolites, such as acetic, lactic, and succinic acid, intestinal barrier dysfunction [lipopolysaccharide (LPS) and LPS-binding protein], an increase in HMGB1, and a concurrent increase in the number of intestinal epithelial cell-derived extracellular vesicles. The ITP improved PTSD symptoms but no changes in intestinal outcomes were noted. This study confirms the intestine is abnormal in subjects with PTSD and suggests that effective treatment of PTSD does not alter intestinal readouts. Targeting beneficial changes in the intestine may be an approach to enhance existing PTSD treatments.NEW & NOTEWORTHY This study confirms an abnormal intestinal environment is present in subjects with PTSD. This study adds to what is already known by examining the intestinal barrier and evaluating the relationship between intestinal readouts and PTSD symptoms and is the first to report the impact of PTSD treatment (which improves symptoms) on intestinal readouts. This study suggests that targeting the intestine as an adjunct approach could improve the treatment of PTSD.

Quantitative analysis of short-chain fatty acids in human plasma and serum by GC-MS.

Short-chain fatty acids (SCFAs) are volatile fatty acids produced by gut microbial fermentation of dietary nondigestible carbohydrates. Acetate, propionate, and butyrate SCFA measures are important to clinical and nutritional studies for their established roles in promoting healthy immune and gut function. Additionally, circulating SCFAs may influence the metabolism and allied function of additional tissues and organs. The accurate quantification of SCFAs in plasma/serum is critical to understanding the biological role of SCFAs. The low concentrations of circulating SCFAs and their volatile nature present challenges for quantitative analysis. Herein, we report a sensitive method for SCFA quantification via extraction with methyl tert-butyl ether after plasma/serum acidification. The organic extract of SCFAs is injected directly with separation and detection using a polar GC column coupled to mass spectrometry. The solvent-to-sample ratio, plasma volume, and amount of HCl needed for SCFA protonation were optimized. Method validation shows good within-day and inter-day repeatability. The limit of detection was 0.3-0.6 µg/mL for acetate and 0.03-0.12 µg/mL for propionate and butyrate. Successful application of this method on clinical plasma and serum samples was demonstrated in six datasets. By simplifying the sample preparation procedure, the present method reduces the risk of contamination, lowers the cost of analysis, increases throughput, and offers the potential for automated sample preparation.

Dietary Regulation of Gut-Brain Axis in Alzheimer's Disease: Importance of Microbiota Metabolites.

Alzheimer's disease (AD) is a neurodegenerative disease that impacts 45 million people worldwide and is ranked as the 6th top cause of death among all adults by the Centers for Disease Control and Prevention. While genetics is an important risk factor for the development of AD, environment and lifestyle are also contributing risk factors. One such environmental factor is diet, which has emerged as a key influencer of AD development/progression as well as cognition. Diets containing large quantities of saturated/trans-fats, refined carbohydrates, limited intake of fiber, and alcohol are associated with cognitive dysfunction while conversely diets low in saturated/trans-fats (i.e., bad fats), high mono/polyunsaturated fats (i.e., good fats), high in fiber and polyphenols are associated with better cognitive function and memory in both humans and animal models. Mechanistically, this could be the direct consequence of dietary components (lipids, vitamins, polyphenols) on the brain, but other mechanisms are also likely to be important. Diet is considered to be the single greatest factor influencing the intestinal microbiome. Diet robustly influences the types and function of micro-organisms (called microbiota) that reside in the gastrointestinal tract. Availability of different types of nutrients (from the diet) will favor or disfavor the abundance and function of certain groups of microbiota. Microbiota are highly metabolically active and produce many metabolites and other factors that can affect the brain including cognition and the development and clinical progression of AD. This review summarizes data to support a model in which microbiota metabolites influence brain function and AD.

Deep nasal sinus cavity microbiota dysbiosis in Parkinson's disease.

Olfactory dysfunction is a pre-motor symptom of Parkinson's disease (PD) that appears years prior to diagnosis and can affect quality of life in PD. Changes in microbiota community in deep nasal cavity near the olfactory bulb may trigger the olfactory bulb-mediated neuroinflammatory cascade and eventual dopamine loss in PD. To determine if the deep nasal cavity microbiota of PD is significantly altered in comparison to healthy controls, we characterized the microbiota of the deep nasal cavity using 16S rRNA gene amplicon sequencing in PD subjects and compared it to that of spousal and non-spousal healthy controls. Correlations between microbial taxa and PD symptom severity were also explored. Olfactory microbial communities of PD individuals were more similar to those of their spousal controls than to non-household controls. In direct comparison of PD and spousal controls and of PD and non-spousal controls, significantly differently abundant taxa were identified, and this included increased relative abundance of putative opportunistic-pathobiont species such as Moraxella catarrhalis. M. catarrhalis was also significantly correlated with more severe motor scores in PD subjects. This proof-of-concept study provides evidence that potential pathobionts are detected in the olfactory bulb and that a subset of changes in the PD microbiota community could be a consequence of unique environmental factors associated with PD living. We hypothesize that an altered deep nasal microbiota, characterized by a putative pro-inflammatory microbial community, could trigger neuroinflammation in PD.

Corrigendum: Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

[This corrects the article DOI: 10.3389/fimmu.2021.686240.].

Attenuated Postprandial GLP-1 Response in Parkinson's Disease.

The incretin hormone glucagon-like peptide 1 (GLP-1) has neuroprotective effects in animal models of Parkinson's disease (PD), and GLP-1 receptor agonists are associated with clinical improvements in human PD patients. GLP-1 is produced and secreted by intestinal L-cells in response to consumption of a meal. Specifically, intestinal microbiota produce short chain fatty acids (SCFA) which, in turn, promote secretion of GLP-1 into the systemic circulation, from which it can enter the brain. Our group and others have reported that PD patients have an altered intestinal microbial community that produces less SCFA compared to age-matched controls. In this report, we demonstrate that PD patients have diminished GLP-1 secretion in response to a meal compared to their household controls. Peak postprandial GLP-1 levels did not correlate with PD disease severity, motor function, or disease duration. These data provide the scientific rationale for future studies designed to elucidate the role of GLP-1 in the pathogenesis of PD and test the potential utility of GLP-1-directed therapies.

Circadian misalignment by environmental light/dark shifting causes circadian disruption in colon.

BACKGROUND: Physiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. Chronic weekly light/dark (LD) shifting (CR disruption; CRD) in mice results in colonic hyperpermeability. However, the mechanisms behind this phenomenon are incompletely understood. One potential innovative in vitro method to study colonic CRs are colon organoids. The goals of this study were to utilize circadian clock gene Per2 luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype. METHODS: Non-shifted (NS) and shifted (S) BL6 Per2::Luc mice were compared after a 22-week experiment. NS mice had a standard 12h light/12h dark LD cycle throughout. S mice alternated 12h LD patterns weekly, with light from 6am-6pm one week followed by shifting light to 6pm-6am the next week for 22 weeks. Mice were tested for intestinal permeability while colon tissue and organoids were examined for CRs of bioluminescence and proteins of barrier function and cell fate. RESULTS: There was no absolute difference in NS vs. S 24h circadian period or phase. However, chronic LD shifting caused Per2::Luc S mice colon tissue to exhibit significantly greater variability in both the period and phase of Per2::Luc rhythms than NS mice colon tissue and organoids. Chronic LD shifting also resulted in increased colonic permeability of the Per2::Luc mice as well as decreased protein markers of intestinal permeability in colonic tissue and organoids from shifted Per2:Luc mice. CONCLUSIONS: Our studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function. These CRD-related changes are stably expressed in colon stem cell derived organoids from CRD mice.

Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.

COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions.

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.